The causal relationship of cigarette smoking with various types of cancer is well documented. Chewing of tobacco and snuff dipping are associated with an increased risk for cancer of the oral cavity and esophagus, as is betel nut chewing together with tobacco. Whole tobacco smoke and its particulate matter are carcinogenic in a number of animal tissues and species; extracts of tobacco and betel quid induce tumors in the skin of mice and the connective tissue of mice and rats. To elucidate important problems in tobacco carcinogenesis we propose the following: I) Development of biochemical assays for the determination of metabolites of the carcinogenic tobacco-specific N-nitrosamines (TSNA) in physiological fluids of tobacco users and for adducts of TSNA-metabolites with hemoglobin in smokers and chewers; II) Development and application of analytical methods for the detection in tobacco products of N-nitrosamides and volatile saturated and unsaturated aldehydes and alpha-ketoaldehydes. Investigations on the formation and high yields of volatile N-nitrosamines in sidestream smoke and their pollution in enclosed environments. III) Study of formation and analysis of carcinogenic areca-specific N-nitrosamines in the saliva of betel quid - tobacco chewers and the conditions favoring and inhibiting their formation; IV) Study of formation, analysis and metabolism of carcinogenic aromatic amines in the smoke of cigarettes, especially of those of the low-yield, nitrate-rich cigarettes; V) Identification of genotoxic flavor compounds in low-yield cigarettes; VI) Study of the tumorigenicity of nicotine-N'-oxides and their occurrence in smokers' urine. VII) Carcinogenicity bioassay of whole sidestream smoke (SS) in hamster inhalation studies and development and application of methodology to determine the uptake of nicotine, HCN, CO by passive smokers and the endogenous formation of N-nitrosoproline upon SS uptake. The results of this program will contribute to our understanding of tobacco carcinogenesis and will also advance the understanding of environmental carcinogenesis in general.